WO1998015272A1 - Procede d'inhibition de proteines kinases activees par contrainte - Google Patents

Procede d'inhibition de proteines kinases activees par contrainte Download PDF

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Publication number
WO1998015272A1
WO1998015272A1 PCT/US1997/018272 US9718272W WO9815272A1 WO 1998015272 A1 WO1998015272 A1 WO 1998015272A1 US 9718272 W US9718272 W US 9718272W WO 9815272 A1 WO9815272 A1 WO 9815272A1
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WO
WIPO (PCT)
Prior art keywords
carbon atoms
hydrogen
lower alkyl
oxygen
adrenoceptor
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PCT/US1997/018272
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English (en)
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WO1998015272A8 (fr
Inventor
Xinkang Wang
Tian-Li Yue
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BOEHRINGER MANNHEIM PHARMACEUTICALS CORP. - SMITHKLINE BEECHAM CORPORATION, LIMITED PARTNERSHIP No.1
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Application filed by BOEHRINGER MANNHEIM PHARMACEUTICALS CORP. - SMITHKLINE BEECHAM CORPORATION, LIMITED PARTNERSHIP No.1 filed Critical BOEHRINGER MANNHEIM PHARMACEUTICALS CORP. - SMITHKLINE BEECHAM CORPORATION, LIMITED PARTNERSHIP No.1
Priority to CA002267967A priority Critical patent/CA2267967A1/fr
Priority to IL12932697A priority patent/IL129326A0/xx
Priority to BR9712283-1A priority patent/BR9712283A/pt
Priority to JP51775498A priority patent/JP2002512591A/ja
Priority to AU47518/97A priority patent/AU4751897A/en
Priority to EP97910045A priority patent/EP0946172A4/fr
Priority to NZ335080A priority patent/NZ335080A/xx
Publication of WO1998015272A1 publication Critical patent/WO1998015272A1/fr
Priority to NO991655A priority patent/NO991655L/no
Publication of WO1998015272A8 publication Critical patent/WO1998015272A8/fr
Priority to AU35040/01A priority patent/AU765934B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a new method of treatment using compounds which are dual non-selective ⁇ -adrenoceptor and oq-adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolam ⁇ ne compounds of Formula I, preferably carvedilol. for inhibiting stress-activated protein kinases (SAPKs).
  • SAPKs stress-activated protein kinases
  • This invention also relates to a method of treatment using compounds which are dual non-selective ⁇ -adrenoceptor and oq-adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolam ⁇ ne compounds of Formula I, preferably carvedilol, for treating diseases mediated by stress-activated protein kinases.
  • SAPKs stress-activated protein kinases
  • JNKs amino- terminal kinases
  • Stress-activated protein kinases activate genes responsible for apoptosis (cell death); SAPK activation precedes the onset of apoptosis.
  • carvedilol a dual non-selective ⁇ - adrenoceptor and cq-adrenoceptor antagonist, inhibits stress-activated protein kinases.
  • This inhibition means that carvedilol and related Formula I compounds are useful in treating diseases mediated by stress-activated protein kinases.
  • this inhibition means that carvedilol and related Formula I compounds are useful for treating SAPK-initiated apoptosis.
  • This inhibition also means that carvedilol and related Formula I compounds are useful for treating cardiovascular diseases, such as ischemia, atherosclerosis, heart failure, and restenosis.
  • the present invention provides a new method of treatment using compounds which are dual non-selective ⁇ -adrenoceptor and oq-adrenoceptor antagonists, in particular the carbazolyl-(4)-oxypropanolamine compounds of Formula I, preferably carvedilol, for inhibiting stress-activated protein kinases, in mammals, particularly humans.
  • the present invention also provides a method of treatment using said compounds for treating diseases mediated by stress-activated protein kinases. Additionally, this invention provides a method for treating SAPK-initiated apoptosis using the compounds of Formula I.
  • This invention further provides a method of treatment using dual non-selective ⁇ -adrenoceptor and oq-adrenoceptor antagonists, in particular carvedilol, in the treatment of cardiovascular disorders, such as ischemia, atherosclerosis, heart failure, and restenosis following angioplasty.
  • the present invention provides a new method for inhibiting stress-activated protein kinases using compounds which are dual non-selective ⁇ -adrenoceptor and oq-adrenoceptor antagonists.
  • this invention provides a new method for inhibiting stress-activated protein kinases using compounds of Formula I:
  • R7-R13 are independently -H or-OH; and A is a moiety of Formula II:
  • Rj is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl;
  • R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl;
  • R3 is hydrogen or lower alkyl of up to 6 carbon atoms
  • R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2-O-;
  • X is a single bond, -CH2, oxygen or sulfur
  • Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl;
  • R5 and Rg are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a -CONH2- group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms, lower alkysulphinyl of up to 6 carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms; or
  • R5 and R together represent methylenedioxy; and pharmaceutically acceptable salts thereof.
  • the present invention provides a new method for inhibiting stress-activated protein kinases using compounds of Formula III:
  • R ⁇ is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl;
  • R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl;
  • R3 is hydrogen or lower alkyl of up to 6 carbon atoms
  • R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2-O-;
  • X is a valency bond, -CH2, oxygen or sulfur
  • Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl;
  • R5 and Rg are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a -CONH2- group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms, lower alkysulphinyl of up to 6 carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms; or
  • R5 and Rg together represent methylenedioxy; and pharmaceutically acceptable salts thereof.
  • the present invention provides a new method for inhibiting stress-activated protein kinases using a compound of Formula IV, better known as carvedilol or (l-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2- propanol):
  • the compounds of the present invention are novel multiple action drugs useful in the treatment of mild to moderate hypertension.
  • Carvedilol is known to be both a competitive non-selective ⁇ -adrenoceptor antagonist and a vasodilator, and is also a calcium channel antagonist at higher concentrations.
  • the vasodilatory actions of carvedilol result primarily from oq-adrenoceptor blockade, whereas the ⁇ -adrenoceptor blocking activity of the drug prevents reflex tachycardia when used in the treatment of hypertension.
  • These multiple actions of carvedilol are responsible for the antihypertensive efficacy of the drug in animals, particularly in humans. See Willette, R.N., Sauermelch, C.F.
  • Carvedilol also markedly reduces infarct size in rat, canine and porcine models of acute myocardial infarction, Ruffolo, R.R., Jr., et al., Drugs of Today, supra, possibly as a consequence of its antioxidant action in attenuating oxygen free radical-initiated lipid peroxidation. Yue, T.-L., et al. supra. Recently, it has been discovered that compounds which are dual non- selective ⁇ -adrenoceptor and oq -adrenoceptor antagonists, in particular the compounds of Formula I, preferably carvedilol, inhibit stress-activated protein kinases.
  • the instant compounds can be used to treat diseases wherein inhibition of stress-activated protein kinases is indicated.
  • the compounds of the present invention preferably carvedilol, can be used for blocking SAPK-induced apoptosis, particularly in cardiac cells or in neuronal cells. Therefore, the compounds of Formula I are useful in treating cardiovascular diseases and neurodegenerative disorders.
  • Some of the compounds of Formula I are known to be metabolites of carvedilol.
  • Certain preferred compounds of the present invention that is, the compounds of Formula I wherein A is the moiety of Formula II wherein Rl is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and one of R ⁇ , R9, or R ⁇ Q is -OH, are metabolites of carvedilol.
  • compositions of the compounds of Formula I may be administered to patients according to the present invention in any medically acceptable manner, preferably orally.
  • the pharmaceutical composition will be in the form of a sterile injectable liquid stored in a suitable container such as an ampoule, or in the form of an aqueous or nonaqueous liquid suspension.
  • suitable container such as an ampoule
  • the nature and composition of the pharmaceutical carrier, diluent or excipient will, of course, depend on the intended route of administration, for example whether by intravenous or intramuscular injection
  • Pharmaceutical compositions of the compounds of Formula I for use according to the present invention may be formulated as solutions or lyophilized powders for parenteral administration.
  • Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation is generally a buffered, isotonic, aqueous solution.
  • suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation.
  • excipients such as ethanol, polyvinyl-pyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • these compounds may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, ethanol, and water.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • the preparation When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
  • Dosing in humans for the treatment of disease according to the present invention should not exceed a dosage range of from about 3.125 to about 50 mg of the compounds of Formula I, particularly carvedilol, preferably given twice daily.
  • the patient should be started on a low dosage regimen of the desired compound of Formula I, particularly carvedilol, and monitered for well-known symptoms of intolerance, e.g., fainting, to such compound.
  • the patient should be brought slowly and incrementally up to the maintenance dose.
  • the choice of initial dosage most appropriate for the particular patient is determined by the practitioner using well-known medical principles, including, but not limited to, body weight.
  • the dosage is doubled at the end of the two weeks and the patient is maintained at the new, higher dosage for two more weeks, and observed for signs of intolerance. This course is continued until the patient is brought to a maintenance dose
  • compositions of this invention will vary according to the particular composition formulated, the mode of administration, the particular site of administration and the host being treated.
  • Carvedilol or propranolol was infused via a syringe pump to give a final concentration of 10 ⁇ M or a concentration indicated when reperfusion was started.
  • Control hearts were perfused for up to 50 minutes after the preequilibration without interruption to the perfusate flow.
  • hearts ventricles were "freeze-clamped” using aluminum tongs precooled in liquid N 2 and pulverized under liquid N,.
  • the powders were resuspended in ice-cold lysis buffer. Extracts were incubated for 5 min at 4°C. The detergent-soluble supernatant fractions were retained, and protein content was measured.
  • SAPK/JNK Stress-activated protein kinase
  • GST-c-Jun ( I1) was made according to the method described by Hibi et al (14).
  • the cDNA clone with a sequence encoding human c-Jun amino acids 1-81 was provided by Human Genome Sciences (HGS)(Gaithesberg, MD) and subcloned into a pGEX 4T-3 which contains a DNA sequence encoding glutathione- S-transferase (GST).
  • the GST-cJun expression vector, pGEX4T-3/c-Jun was transformed into E.Coli.
  • Expression of GST-c-Jun (1 81) fusion protein was induced by isopropyl- ⁇ -thiogalactoside (IPTG). E.Coli were lysed and centrifuged.
  • the fusion protein, GST-c-Jun (l 81) was purified by glutathione-Sepharose chromatography.
  • detergent-soluble extracts 100 ⁇ L, 0.5 mg protein were added to 4 ⁇ of GST-c Jun, 8] . After incubation (4°C, 1 hour), glutathione-Sepharose was added, and the incubation was continued with mixing (4°C, 1 hour).
  • Pellets were washed in lysis buffer A containing 75 mmol/L NaCl, then in buffer A (mmol/L: HEPES 20, MgCl2 2.5, EDTA 0.1, and ⁇ - glycerophosphate 20, pH 7.7) containing 75 mmol/L NaCl and 0.05% (vol/vo/) Triton X-100, and finally in buffer A alone. Phosphorylation of GST-c Jun,.
  • kinase assay buffer mmol/L: HEPES 20, MgCl 2 20, ⁇ -glycerophosphate 20, DTT 2, and Na3 VO 4 0.1, pH 7.6 containing 20 ⁇ mol L ATP and 1 to 2 ⁇ Ci [y- 32 P] ATP (Amersham International). After 20 minutes at 30°C, the reaction was terminated by centrifugation. The pellet was washed in cold buffer A containing 75 mmol/L NaCl and 0.05% (vol/vol) Triton X-100. Phosphorylated proteins in the pellet were eluted by boilingin SDS-PAGE sample buffer and then separated by SDS-PAGE. Gels were stained with Coomassie blue to identifythe 46-kD GST-c-Jun, .gr After autoradiography phosplorlmager was used to quantify the band intensities of c-Jun,.,,.
  • Carvedilol administered at the beginning of reperfusion reduced the activation of SAPK by 51.2% and 30.7% at 1 and 10 ⁇ M, respectively. Under the same condition, propranolol, at 10 ⁇ M, had no effect on SAPK activation by ischemia-reperfusion as shown in Fig. 2.

Abstract

L'invention concerne un procédé d'inhibition de protéines kinases activées par contrainte comprenant l'administration à un mammifère présentant un besoin de ces protéines, d'une dose substantielle d'un composé consistant en un antagoniste dual non sélectif β-adrénorécepteur et α1-adrénorécepteur.
PCT/US1997/018272 1996-10-09 1997-10-09 Procede d'inhibition de proteines kinases activees par contrainte WO1998015272A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
CA002267967A CA2267967A1 (fr) 1996-10-09 1997-10-09 Procede d'inhibition de proteines kinases activees par contrainte
IL12932697A IL129326A0 (en) 1996-10-09 1997-10-09 Method for inhibiting stress-activated protein kinases
BR9712283-1A BR9712283A (pt) 1996-10-09 1997-10-09 Método para inibir as cinases de proteìnas ativadas por tensão
JP51775498A JP2002512591A (ja) 1996-10-09 1997-10-09 ストレス活性化されたタンパク質キナーゼの阻害法
AU47518/97A AU4751897A (en) 1996-10-09 1997-10-09 Method for inhibiting stress-activated protein kinases
EP97910045A EP0946172A4 (fr) 1996-10-09 1997-10-09 Procede d'inhibition de proteines kinases activees par contrainte
NZ335080A NZ335080A (en) 1996-10-09 1997-10-09 Use of dual non-selective beta-adrenoceptor and alpha1-adrenoceptor for inhibiting stress activated protein kinases(SAPK)
NO991655A NO991655L (no) 1996-10-09 1999-04-08 FremgangsmÕte for Õ inhibere stress-aktiverte-proteinkinaser
AU35040/01A AU765934B2 (en) 1996-10-09 2001-04-06 Method for inhibiting stress-activated protein kinases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US2845996P 1996-10-09 1996-10-09
US60/028,459 1996-10-09

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US09/456,866 Continuation US6214854B1 (en) 1996-10-09 1999-12-08 Method for inhibiting stress-activated protein kinases

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WO1998015272A1 true WO1998015272A1 (fr) 1998-04-16
WO1998015272A8 WO1998015272A8 (fr) 2000-03-23

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US (1) US6214854B1 (fr)
EP (1) EP0946172A4 (fr)
JP (1) JP2002512591A (fr)
KR (1) KR20000048967A (fr)
CN (1) CN1157188C (fr)
AU (1) AU4751897A (fr)
BR (1) BR9712283A (fr)
CA (1) CA2267967A1 (fr)
CZ (1) CZ123099A3 (fr)
IL (1) IL129326A0 (fr)
NO (1) NO991655L (fr)
NZ (1) NZ335080A (fr)
PL (1) PL332638A1 (fr)
TR (1) TR199900762T2 (fr)
WO (1) WO1998015272A1 (fr)
ZA (1) ZA979055B (fr)

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JP5072364B2 (ja) * 2003-11-25 2012-11-14 スミスクライン ビーチャム （コーク） リミテッド カルベジロール遊離塩基、カルベジロール塩、無水形態またはその溶媒和物、対応する医薬組成物、制御放出処方および治療またはデリバリー方法
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Chemical Abstracts Service (C A S); 1 January 1994 (1994-01-01), YUE, TIAN LI, ET AL: "SB 211475, A METABOLITE OF VARVEDILOL, A NOVEL ANTIHYPERTENSIVE AGENT, IS A POTENT ANTIOXIDANT", XP002909852, Database accession no. 120-235718A *
Chemical Abstracts Service (C A S); 1 January 1995 (1995-01-01), OHTA HIDEKI, ET AL: "A POSSIBLE ROLE OF SPHINGOSINE IN INDUCTION OF APOPTOSIS BY TUMOR FACTOR ALPHA IN HUMAN NEUTROPHILS", XP002909855, Database accession no. 122-29762Y *
Chemical Abstracts Service (C A S); 1 January 1996 (1996-01-01), BRUNVAND H, ET AL: "CARVEDILOL PROTECTS AGAINST LETHAL REPERFUSION INJURY THROUGH ANTIADRENERGIC MECHANISMS", XP002909856, Database accession no. 125-238026N *
See also references of EP0946172A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001041767A1 (fr) * 1999-12-07 2001-06-14 Duke University UTILISATION DE MEDICAMENTS PRESENTANT UNE SELECTIVITE POUR UN SOUS-TYPE DE α1 AR CHEZ DES PATIENTS ATTEINTS D'UN INFARCTUS DU MYOCARDE AIGU
US6921773B2 (en) 1999-12-07 2005-07-26 Duke University Use of α-1AR subtype-selective drugs in patients with acute myocardial infarction

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US6214854B1 (en) 2001-04-10
KR20000048967A (ko) 2000-07-25
CA2267967A1 (fr) 1998-04-16
ZA979055B (en) 1999-05-10
EP0946172A4 (fr) 2002-05-22
IL129326A0 (en) 2000-02-17
JP2002512591A (ja) 2002-04-23
NO991655L (no) 1999-06-08
BR9712283A (pt) 1999-08-31
TR199900762T2 (xx) 1999-07-21
CZ123099A3 (cs) 1999-11-17
NO991655D0 (no) 1999-04-08
AU4751897A (en) 1998-05-05
NZ335080A (en) 2000-04-28
PL332638A1 (en) 1999-09-27
EP0946172A1 (fr) 1999-10-06
WO1998015272A8 (fr) 2000-03-23
CN1239888A (zh) 1999-12-29
CN1157188C (zh) 2004-07-14

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